Dock-and-lock (DNL) complexes for therapeutic and diagnostic use

Abstract

Disclosed herein are methods and compositions dock and lock (DNL) complexes comprising an AD moiety selected from an AKAP protein and a DDD moiety selected from a protein kinase A regulatory subunit. Also disclosed are fusion proteins comprising an AD moiety or DDD moiety attached to an effector moiety. The DDD moieties form dimers that bind to the AD moiety to form the DNL complexes. The effector moieties may be selected from a wide range of known effector moieties that produce one or more physiological effects, including but not limited to cell death. The DNL complexes may further comprise one or more diagnostic and/or therapeutic agents. The DNL complexes are of use for treating and/or diagnosing a variety of diseases or conditions.

What is claimed is: 
     
       1. An isolated DNL complex comprising:
 a) a first fusion protein comprising (i) an antibody or antigen binding fragment thereof that binds to a human antigen selected from the group consisting of carbonic anhydrase IX, CCL19 (C-C motif chemokine ligand 19), CCL21(C-C motif chemokine ligand 21), CD1, CD1a, CD2, CD3, CD4, CD5, CD8, CD11A, CD14, CD15, CD16, CD18, CD19, IGF-1R, CD20, CD21, CD22, CD23, CD25, CD29, CD30, CD33, CD37, CD38, CD40, CD40L, CD45, CD46, CD52, CD54, CD55, CD59, CD64, CD70, CD74, CD79a, CD80, CD83, CD95, CD126, CD138, CD147, CD154, AFP, PSMA, CEACAM5, CEACAM6, B7, ED-B fibronectin, Flt-1 (Fms-like tyrosine kinase 1), Flt-3, folate receptor, HMGB-1 (high mobility group protein B1), hypoxia inducible factor (HIF), insulin-like growth factor-1 (IGF-1), IFN-γ, IL-2, IL-4R, IL-6R, IL-13R, IL-15R, IL-17R, IL-18R, IL-6, IL-8, IL-12, IL-15, IL-17, IL-18, MAGE, mCRP, MCP-1, MIP-1A, MIP-1B, MIF, MUC1, MUC2, MUC3, MUC4, NCA-95, EGP-1, EGP-2, HLA-DR, tenascin, Le(y), RANTES, Tn (Thomsen-nouvelle) antigen, TNF-α, VEGF, EGFR, PlGF, complement factor C3a, complement factor C3b, complement factor C5a, and complement factor C5, and (ii) an AD (anchoring domain) moiety, wherein the amino acid sequence of the AD moiety is from the anchoring domain of an AKAP (A-kinase anchoring protein); and 
 b) a second fusion protein comprising (iii) an immunomodulator, and (iv) a DDD (dimerization and docking domain) moiety, wherein the amino acid sequence of the DDD moiety is residues 1-44 of human protein kinase A regulatory subunit RIIα, wherein the immunomodulator is selected from the group consisting of, erythropoietin, thrombopoietin, granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), interferon-α, interferon-β, interferon-γ, stem cell growth factor designated “S1 factor”, human growth hormone, N-methionyl human growth hormone, bovine growth hormone, parathyroid hormone, thyroxine, insulin, proinsulin, relaxin, prorelaxin, follicle stimulating hormone (FSH), thyroid stimulating hormone (TSH), luteinizing hormone (LH), hepatic growth factor, prostaglandin, fibroblast growth factor, prolactin, placental lactogen, OB protein, mullerian-inhibiting substance, mouse gonadotropin-associated peptide, inhibin, activin, vascular endothelial growth factor, integrin, NGF-β, platelet-growth factor, TGF-α, TGF-β, insulin-like growth factor-I, insulin-like growth factor-II, macrophage-CSF (M-CSF), IL-1, IL-1α, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-18, IL-21, thrombospondin, and endostatin; 
 
       wherein two copies of the DDD moiety form a dimer that binds to one copy of the AD moiety to form the DNL complex.